1. Field of the Invention
The present invention refers to a process for the preparation of aqueous formulations for ophthalmic use. Specifically, the present invention relates to a process for preparing ophthalmic formulations containing azithromycin, as well any formulations obtained through a such process, and their ophthalmic use against ocular bacterial infections caused by gram-positive and gram-negative pathogens (e.g. Staphylococcus spp., Streptococcus spp., Haemophilus influenzae, Pseudomonas aeruginosa, Serratia marcescens, Klebsiella pneumoniae, Enterobacter, Citrobacter, Chlamydia spp.) as well as from other microorganisms generally involved in the most common ocular infections (e.g. conjunctivitis, keratitis and blepharitis).
2. Description of the Background
Azithromycin (U.S. Pat. No. 4,517,359) is a well-known antibiotic belonging to the macrolide class (of which erythromycin is the precursor), antibiotics having a structural similarity, most of them isolated from fermentation of Streptomices spp., and essentially utilized in the treatment of the skin and soft tissue infections caused by gram-positive organisms, even though the spectrum of action of the newer macrolides also includes some gram-negative organisms (e.g. Haemophilus influenzae). Notwithstanding the structural similarity, azithromycin can be considered as unique within the macrolides class, such as to be included in a new class of antibiotics known as azalides. In particular, the specific characteristics of azithromycin make this molecule more stable, tolerated and effective than its precursor erythromycin (S. Alvarez-Elcoro, M. J. Enzler, "The macrolides: Erythromycin, clarithromycin, and azithromycin", Mayo Clinic Proceeding, 1999, 74: 613-634).
In fact, erythromycin and its salt derivatives (e.g. erythromycin lactobionate, erythromycin glucoheptonate, erythromycin estolate, erythromycin succinate etc.) have often been shown unstable in acidic medium and physiological conditions as well, by causing degradation products in microbiologically-inactive structures [P. J. Atkins et al., "Kinetic studies on the decomposition of erithromycin A in aqueous acidic and neutral buffers", Int. J. Pharmaceutics, 1986, 30: 199-207; E. Fieser, S. H. Steffen "Comparison of the acid stability of azithromycin and erithromycin A", J. Antimicrob. Chemother., 1990, (Suppl. A) 25: 39-47; M. M. Amer, K. F. Takla "Studies on the stability of some pharmaceutical formulations. V-stability of erythromycin", Bulletin of the Faculty of Pharmacy Cairo University].
In addition azithromycin, even in comparison to other recent macrolides, shows a superior antibacterial activity against some gram-negative organisms, while retaining the same efficacy against gram-positive organisms, moreover azithromycin, with respect to other macrolides, has an extensive intracellular distribution into specific tissues after oral administration (R. P. Glaude et al., Antimicrob. Agents and Chemother., 1989, 33(3): 277-82). Half-life of azithromycin is so extremely elevated such as to be considered an excellent antibiotic, after a once-daily administration, against infections of the respiratory tract, skin and soft tissues [A. P. Ball et al., J. Int. Med. Res., 1991, 19(6): 446-50; A. E. Girard et al., Antimicrob. Agents and Chemother., 1987, 31(12): 1948-1954].
Furthermore, it is also possible to administer azithromycin, by systemic route, in a variety of preparations and pharmaceutical forms. However, even though the characteristics of this molecule are such as to privilege its use as antibacterial in the topical ocular administration as well, so far it has been failed to prepare aqueous formulations for ophthalmic use, containing azithromycin, stable and compatible to the ocular structures.
Among the major difficulties to overcome, in providing an aqueous ophthalmic preparation of azithromycin, is the poor water solubility of this molecule together with safety problems resulting from the potential ophthalmic use of one of its salts, obtained by applying classical criteria of chemical synthesis, wherein the purification of the organic solvents being utilized, harmful to the ocular structures, is extremely difficult and often not completely resoluble.
As an example, EP-B-0677530 and U.S. Pat. No. 4,474,768 patents describe the preparation of different azithromycin salt derivatives, in presence of organic solvents, pharmaceutically acceptable, wherein before utilizing them in therapy, through pharmaceutical forms usually administered as oral or other incompatible forms with the topical ophthalmic use, their purification methods have to be repeated many times. It has also been described how is unlikely to overcome the difficulties of pharmaceutical type, essentially because of the poor aqueous solubility of macrolides (V. Andrews, "Antibiotic treatment of ophthalmic infection: new developments", J. Hospital Infection, 1995, 30: 268-274), and, although their acquisition in ophthalmic therapy has been wished, unless to rely on ophthalmic forms (e.g ointment) less bioavailable and which, anyway, it would make necessary their combination with eye drops of the same active principle, this in order to completely eradicate after treatment any pathogen distributed into the ocular surface.
Numerous publications describe the pharmacokinetics of azithromycin after oral administration together with its potential application to treat infections of the ocular structures [K. F. Tabbara et al., "Ocular levels of azithromycin", Arch Ophthalmol., 1998, 116(12): 1625-1628; Z. A. Karcioglu et al., "Pharmacokinetics of azithromycin in rabbit lachrymal glands and conjunctiva", Ophthalmic. Res., 1999, 31(1): 47-52; K. F. Tabbara et al., "Single-dose azithromycin in the treatment of trachoma. A randomized controlled study" Ophthalmology, 1996, 103(5): 842-846; D. M. O'Day et al., "Ocular pharmacokinetics of orally administered azithromycin in rabbits", J. Ocular Pharmacol. 1994, 10(4): 633-641; Z. A. Karcioglu et al., "Pharmacokinetics of azithromycin in trachoma patients: serum and tear levels", Ophthalmology, 1998, 105(4): 658-661]; however, under no circumstances the oral formulations utilized are able to make sure an effective tissue concentration of azithromycin into the ocular surface, what it would occur by administering topically the active principle in the elective pharmaceutical form of eye drops.
Whether from one side the synthesis of azithromycin salt derivatives has been improved or in some other instances it has been tried to increase the bioavailability as well as the activity through oral administration by adopting controlled release systems, see U.S. Pat. No. 5,705,190 referred to clarithromycin, from the other hand it has not been able to obtain similar results in preparing stable aqueous formulations, containing azithromycin, to be utilized as effective and safe products in the antimicrobial therapy of ocular infections.